Gene expression markers for prediction of patient response to chemotherapy
Inventors
Baker, Joffre B. • Cowens, Wayne • Langone, Kim • Hackett, James • Watson, Drew • Paik, Soonmyung
Assignees
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Publication Number
US-8632980-B2
Publication Date
2014-01-21
Expiration Date
Abstract
The present invention relates to gene sets useful in assessing prognosis and/or predicting the response of cancer, e.g. colorectal cancer to chemotherapy. In addition, the invention relates to a clinically validated cancer test, e.g. colorectal test, for assessment of prognosis and/or prediction of patient response to chemotherapy, using expression analysis. The present invention accommodates the use of archived paraffin embedded biopsy material for assay of all markers in the relevant gene sets and therefore is compatible with the most widely available type of biopsy material.
Core Innovation
The disclosed invention relates to predicting whether a human patient diagnosed with colorectal cancer has an increased or decreased likelihood of a positive clinical response to chemotherapy. The approach uses extracting RNA from a fixed, paraffin-embedded colorectal cancer tissue sample obtained from the patient, and quantitatively measuring an RNA transcript of HNRPD.
The measured HNRPD level is normalized to obtain a normalized HNRPD expression level or a normalized HNRPD amplicon level, and a computer-implemented program compares the normalized level to a statistical model-predicted relationship. The relationship is determined from populations of colorectal cancer patients with known clinical outcome, and a report is generated comprising a prediction whether the patient has an increased or decreased likelihood of exhibiting a positive response.
The examples further describe a 375-gene RT-PCR gene panel with reference genes and reference-normalized expression, together with univariate Cox proportional hazard models for recurrence-free interval. Gene-by-treatment interaction results are presented for identifying genes predictive of response to 5-FU/LV versus surgery-only, and co-expression clustering is introduced to find genes co-expressed with prognostic/predictive genes.
Claims Coverage
Two independent claims are present. Across the independent claims, the inventive features include using fixed, paraffin-embedded tissue RNA to measure HNRPD and comparing normalized HNRPD measurements to a population-derived statistical model to generate a prediction report of increased or decreased likelihood of positive chemotherapy response, with clinical response expressed using specified intervals.
Predicting chemotherapy response using normalized HNRPD RNA from fixed, paraffin-embedded colorectal tissue
extracting RNA from a fixed, paraffin-embedded colorectal cancer tissue sample obtained from the patient; quantitatively measuring a level of an RNA transcript of HNRPD; normalizing the level of the RNA transcript of HNRPD to obtain a normalized HNRPD expression level; using a computer-implemented program to compare the normalized HNRPD expression level to a statistical model-predicted relationship determined from populations with known clinical outcome; and generating a report comprising a prediction whether the patient has an increased or decreased likelihood of exhibiting a positive response to chemotherapy.
Ct/amplicon-based HNRPD assay with reference-normalization and model comparison
extracting RNA from a fixed, paraffin-embedded colorectal cancer tissue sample; reverse transcribing and amplifying an RNA transcript of HNRPD to produce an amplicon; quantitatively assaying a level of the HNRPD amplicon; normalizing the HNRPD amplicon level against a level of an amplicon of at least one reference RNA transcript to provide a normalized HNRPD amplicon level; comparing the normalized HNRPD amplicon level to a statistical model-predicted relationship determined from populations with known clinical outcome using a computer-implemented program; and generating a report comprising a prediction whether the patient has an increased or decreased likelihood of a positive clinical response to treatment with chemotherapy, wherein the clinical response is expressed in terms of Recurrence-Free Interval (RFI), Overall Survival (OS), Disease-Free Survival (DFS), or Distant Recurrence-Free Interval (DRFI).
The independent claims cover measuring an HNRPD RNA transcript from fixed, paraffin-embedded colorectal tissue with normalization and statistical-model comparison to predict increased or decreased likelihood of positive chemotherapy response, and an amplicon/RT-based implementation with reference transcript normalization and model comparison, with response outcome expressed using RFI, OS, DFS, or DRFI.
Stated Advantages
Documented Applications
Predicting whether a human patient diagnosed with colorectal cancer has an increased or decreased likelihood of a positive clinical response to treatment with chemotherapy, with clinical response expressed in terms of RFI, OS, DFS, or DRFI.
Identifying genes predictive of response to 5-FU/LV versus surgery-only using gene-by-treatment interaction results, and using co-expression clustering to find genes co-expressed with prognostic/predictive genes that can be assayed as substitutes or in combination.
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